Description:

Patients with symptomatic heart failure (HF) and normal to near-normal ejection fraction (EF) have different pathophysiological alterations compared with those with HF and low EF, and current therapies for this condition are limited. Basic science studies have demonstrated that plasma renin activity is enhanced in patients with HF and normal EF. Accordingly, the I-PRESERVE study sought to evaluate the effect of angiotensin-receptor blockade with irbesartan on cardiovascular outcomes in these patients.

Contribution to the Literature: The I-PRESERVE trial showed that irbesartan does not influence cardiovascular mortality and morbidity in patients with HF and preserved EF compared with placebo.

Patient Populations:

Exclusions:

Alternative explanation for patient’s symptoms, such as pulmonary disease

LVEF <40%

History of acute coronary syndrome, coronary revascularization, or stroke within the past 3 months

Substantial valvular heart disease

Hypertrophic or restrictive cardiomyopathy

Pericardial disease

Chronic obstructive pulmonary disease, other causes of right HF

Systolic blood pressure <100 or >160 mm Hg

Diastolic blood pressure >95 mm Hg

Life expectancy <3 years

Liver function abnormalities

Anemia (hemoglobin <11 g%)

Creatinine >2.5 mg/dl

Primary Endpoints:

Composite of all-cause mortality and hospitalization for cardiovascular causes

Secondary Endpoints:

All-cause mortality

Hospitalization for cardiovascular causes

Death due to worsening congestive heart failure (CHF) or sudden death or hospitalization due to worsening CHF

Change in the total score on the Minnesota Living with Heart Failure scale at 6 months

Change in plasma level of NT-proBNP at 6 months

Vascular event (cardiovascular death, nonfatal MI, nonfatal stroke)

Cardiovascular death

Drug/Procedures Used:

Patients were started on irbesartan 75 mg daily, or placebo. The dose was doubled to 150 mg daily after 1-2 weeks, and then doubled again to 300 mg daily after another 1-2 weeks, as per a forced-titration protocol.

Principal Findings:

A total of 4,128 patients were randomized, 2,067 to irbesartan, and 2,061 to placebo. Baseline characteristics were fairly similar between the four groups. The majority of patients had heart failure from hypertension (64%), and one-quarter had ischemic cardiomyopathy (25%). The baseline left ventricular EF (LVEF) was about 60%, and the majority of patients had New York Heart Association (NYHA) class III symptoms (77%). About 44% of the patients had been hospitalized for HF within the preceding 6 months. Moderate to severe diastolic dysfunction was present in only 7% of the patients. About 29% had atrial fibrillation, 28% had diabetes, and 89% had hypertension. Median baseline N-terminal B-type natriuretic peptide (NT-proBNP) was about 340 pg/ml.

Irbesartan was associated with a mean decrease in systolic and diastolic blood pressure by 3.8/2.1 mm Hg, as compared with 0.2/0.2 mm Hg in the placebo group. There was no difference between the irbesartan and placebo groups in the incidence of the primary outcome of all-cause mortality or hospitalization for cardiovascular causes (36% vs. 37%, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.86-1.05, p = 0.35). Similarly, there was no difference between the two groups in the incidence of mortality (10.7% vs. 10.7%, p = 0.98), cardiovascular hospitalizations (25.2% vs. 26.1%, p = 0.44), worsening HF (14.1% vs. 15.2%, p > 0.05), or ventricular arrhythmias (0.24% vs. 0.15%, p > 0.05). Quality of life improved in both groups at the end of 6 months, and was not significantly different between the two groups. The median levels of change in NT-proBNP from baseline were also not significantly different between the two groups (13 vs. 2 pg/ml, p = 0.14).

The rate of study drug discontinuation was high in both arms (33%). There was no difference in the mean levels of creatinine between the two groups at the end of the study, although a doubling of creatinine occurred more often with irbesartan compared with placebo (6% vs. 4%, p < 0.0001). Similarly, serious hyperkalemia (serum K >6 mmol/L) occurred more often with irbesartan (3% vs. 2%, p = 0.01). The incidence of hypotension was similar between the two groups (3% vs. 3%, p = 0.84).

Epidemiology for hospitalization in patients with HF and preserved EF: Of the total cohort, 2,278 patients had 5,863 hospitalizations during the 49 months of follow-up, of which 3,585 (61%) were recurrent hospitalizations. For any-cause hospitalizations, 26.5% of patients died during follow-up, with an incident mortality rate of 11.1 deaths per 100 patient-years (PYs). Just over half of the rehospitalizations (53.6%) were classified as cardiovascular, of which HF was the most common cause. The incident mortality following a HF admission was 19.3 deaths per 100-PY, and for a non-HF admission was 8.7 deaths per 100 PY. The risk for death was highest in the first 30 days.

Interpretation:

The results of the I-PRESERVE trial indicate that angiotensin-receptor blockade with irbesartan is not associated with a reduction in cardiovascular mortality and morbidity in patients with HF and normal EF, with an increase in the incidence of observed adverse effects, including serious hyperkalemia.

These results are similar to those noted in the CHARM-Preserved trial with candesartan, and the PEP-CHF trial with perindopril. The effects of angiotensin-receptor blockade in this trial may have been diluted by the fact that 25% of the patients were also on ACE inhibitors, and 15% were on spironolactone, both of which also impact the renin-angiotensin system. Another reason for the negative findings of this trial could be that other pathophysiological mechanisms may be involved in this subset of patients with heart failure, since this entity is not very well understood, even from a basic science perspective.

From an epidemiological standpoint, patients with HF and preserved EF have a high hospitalization burden, especially for HF, with high associated mortality. Efforts to reduce cardiovascular morbidity and mortality in this patient population are urgently needed.